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Posts Tagged ‘MD Anderson’


New Risk Stratification for Breast Cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

MD Anderson Researchers Develop New Breast Cancer Staging System

https://www.genomeweb.com/cancer/md-anderson-researchers-develop-new-breast-cancer-staging-system

NEW YORK (GenomeWeb) – Researchers at the University of Texas MD Anderson Cancer Center have developed a new breast cancer staging system that incorporates tumor biology as a critical prognostic indicator for women who undergo neoadjuvant therapy.

Published this week in JAMA Oncology, the Neo-Bioscore staging system incorporates HER2/ERBB2 status, which allows for more precise prognostic stratification of all breast cancer subtypes.

To date, breast cancer patient staging involved considering the size of the primary tumor, metastasis, or disease in the lymph nodes at the time of presentation as the primary factors.However, this fails to take into account the biology of the tumor, which has shown to be critically important, Elizabeth Mittendorf, associate professor of Breast Surgical Oncology at MD Anderson and corresponding author on the study, said in a statement.

The new system builds on the development of an earlier breast cancer staging system developed by MD Anderson, CPS+EG, that incorporates preclinical stage, estrogen receptor status, grade, and post-treatment pathologic stage. While it was an improvement from previous methods, it is no longer a sufficient staging system because it predates the routine use of trastuzumab in the neoadjuvant setting and therefore had a limited ability to provide prognostic information for HER2/ERBB2-positive patients, Mittendorf said.

To develop the staging system, the researchers conducted a retrospective study that evaluated 2,377 MD Anderson breast cancer patients who all had non-metastatic invasive breast cancer and were treated with neoadjuvant chemotherapy.

Each patient’s clinicopathologic data were recorded, including age, clinical and pathological stage, ER status, HER2/ERBB2 status, and nuclear grade. Patients’ ER status was recorded as a percentage of cells staining positive under immunohistochemical analysis. Their ERBB2 status was defined as positive at a reading of 3+ on immunohistochemical analysis or when gene amplification was shown on fluorescence in situ hybridization.

All patients received an anthracycline and/or taxane-based neoadjuvant chemotherapy regimen. Patients with HER2/ERBB2-positive disease routinely completed one year of trastuzumab therapy. After completing chemotherapy, patients underwent either breast-conserving therapy or mastectomy with axillary evaluation with or without post-mastectomy irradiation.

Patients’ CPS+EG score was determined according to the previously published staging system and was calculated twice (once using 1 percent or higher as the cutoff for ER positivity and again using 10 percent or higher as the cutoff).

Their disease-specific survival (DSS) was also calculated using multiple staging systems: AJCC clinical stage, AJCC pathologic stage, CPS+EG (1 percent cutoff), and CPS+EG (10 percent cutoff). Within each staging system, DSS among subgroups was compared using the log-rank test.

After the researchers determined a CPS+EG score for each patient, they added the patient’s respective HER2/ERBB2 status to the model. They then constructed the novel staging system by adding a point to the CPS+EG score for HER2-negative tumors. In the study cohort, 591 patients were HER2/ERBB2 positive.

The researchers found that in addition to validating previous findings that CPS+EG score improved prognostication of patients, the Neo-Bioscore created a more refined stratification in approximately 75 percent of the study cohort. This shift reflects the number of HER2/ERBB2-negative tumors in the study and demonstrated that adding HER2/ERBB2 standards created a highly significant improvement.

“With this tool, I can give my patients the precise information they are looking for: a more refined prognosis. Also, with this data, we will know which patients are in greatest need of additional therapy,” Mittendorf said. “Hopefully these findings will result in more informed conversations between doctor and patient.”

 

The Neo-Bioscore Update for Staging Breast Cancer Treated With Neoadjuvant ChemotherapyIncorporation of Prognostic Biologic Factors Into Staging After Treatment 

Elizabeth A. Mittendorf, MD, PhD1; Jose Vila, MD1; Susan L. Tucker, PhD2; ….; W. Fraser Symmans, MD6; Aysegul A. Sahin, MD6; Gabriel N. Hortobagyi, MD3; Kelly K. Hunt, MD
JAMA Oncol. Published online March 17, 2016.              http://dx.doi.org:/10.1001/jamaoncol.2015.6478

Importance  We previously described and validated a breast cancer staging system (CPS+EG, clinical-pathologic scoring system incorporating estrogen receptor–negative disease and nuclear grade 3 tumor pathology) for assessing prognosis after neoadjuvant chemotherapy using pretreatment clinical stage, posttreatment pathologic stage, estrogen receptor (ER) status, and grade. Development of the CPS+EG staging system predated routine administration of trastuzumab in patients with ERBB2-positive disease (formerly HER2 or HER2/neu).

Objective  To validate the CPS+EG staging system using the new definition of ER positivity (≥1%) and to develop an updated staging system (Neo-Bioscore) that incorporates ERBB2 status into the previously developed CPS+EG.

Design, Setting, and Participants  Retrospective review of data collected prospectively from January 2005 through December 2012 on patients with breast cancer treated with neoadjuvant chemotherapy at The University of Texas MD Anderson Cancer Center.

Main Outcomes and Measure  Prognostic scores were computed using 2 versions of the CPS+EG staging system, one with ER considered positive if it measured 10% or higher, the other with ER considered positive if it measured 1% or higher. Fits of the Cox proportional hazards model for the 2 sets of prognostic scores were compared using the Akaike Information Criterion (AIC). Status of ERBB2 was added to the model, and the likelihood ratio test was used to determine improvement in fit.

Results  A total of 2377 patients were included; all were women (median age, 50 years [range, 21-87 years]); ER status was less than 1% in 28.9%, 1% to 9% in 8.3%, and 10% or higher in 62.8%; 591 patients were ERBB2 positive. Median follow-up was 4.2 years (range, 0.5-11.7 years). Five-year disease-specific survival was 89% (95% CI, 87%-90%). Using 1% or higher as the cutoff for ER positivity, 5-year disease-specific survival estimates determined using the CPS+EG stage ranged from 52% to 98%, thereby validating our previous finding that the CPS+EG score facilitates more refined categorization into prognostic subgroups than clinical or final pathologic stage alone. The AIC value for this model was 3333.06, while for a model using 10% or higher as the cutoff for ER positivity, it was 3333.38, indicating that the model fits were nearly identical. The improvement in fit of the model when ERBB2 status was added was highly significant, with 5-year disease-specific survival estimates ranging from 48% to 99% (P < .001). Incorporating ERBB2 into the staging system defined the Neo-Bioscore, which provided improved stratification of patients with respect to prognosis.

Conclusions and Relevance  The Neo-Bioscore improves our previously validated staging system and allows its application in ERBB2-positive patients. We recommend that treatment response and biologic markers be incorporated into the American Joint Committee on Cancer staging system.

 

Transforming Breast Cancer Treatment

Landmark preclinical study cured lung metastases in 50 percent of breast cancers by making nanoparticles inside the tumor.

http://www.technologynetworks.com/news.aspx?ID=189462

A team of investigators from Houston Methodist Research Institute may have transformed the treatment of metastatic triple negative breast cancer by creating the first drug to successfully eliminate lung metastases in mice.

The majority of cancer deaths are due to metastases to the lung and liver, yet there is no cure. Existing cancer drugs provide limited benefit due to their inability to overcome biological barriers in the body and reach the cancer cells in sufficient concentrations. Houston Methodist nanotechnology and cancer researchers have solved this problem by developing a drug that generates nanoparticles inside the lung metastases in mice.

In this study, 50 percent of the mice treated with the drug had no trace of metastatic disease after eight months. That’s equivalent to about 24 years of long-term survival following metastatic disease for humans.

Due to the body’s own defense mechanisms, most cancer drugs are absorbed into healthy tissue causing negative side effects, and only a fraction of the administered drug actually reaches the tumor, making it less effective, said Mauro Ferrari, Ph.D, president and CEO of the Houston Methodist Research Institute. This new treatment strategy enables sequential passage of the biological barriers to transport the killing agent into the heart of the cancer. The active drug is only released inside the nucleus of the metastatic disease cell, avoiding the multidrug resistance mechanism of the cancer cells. This strategy effectively kills the tumor and provides significant therapeutic benefit in all mice, including long-term survival in half of the animals.

This finding comes 20 years after Ferrari started his work in nanomedicine. Ferrari and Haifa Shen, M.D., Ph.D., are co-senior authors on the paper, which describes the action of the injectable nanoparticle generator (iNPG), and how a complex method of transporting a nano-version of a standard chemotherapy drug led to never before seen results in mice models with triple negative breast cancer that had metastasized to the lungs.

“This may sound like science fiction, like we’ve penetrated and destroyed the Death Star, but what we discovered is transformational. We invented a method that actually makes the nanoparticles inside the cancer and releases the drug particles at the site of the cellular nucleus. With this injectable nanoparticle generator, we were able to do what standard chemotherapy drugs, vaccines, radiation, and other nanoparticles have all failed to do,” said Ferrari.

Houston Methodist has developed good manufacturing practices (GMP) for this drug and plans to fast-track the research to obtain FDA-approval and begin safety and efficacy studies in humans in 2017.

“I would never want to overpromise to the thousands of cancer patients looking for a cure, but the data is astounding,” said Ferrari, senior associate dean and professor of medicine, Weill Cornell Medicine. “We’re talking about changing the landscape of curing metastatic disease, so it’s no longer a death sentence.”

The Houston Methodist team used doxorubicin, a cancer therapeutic that has been used for decades but has adverse side effects to the heart and is not an effective treatment against metastatic disease. In this study, doxorubicin was packaged within the injectable nanoparticle generator that is made up of many components.

Shen, a senior member of the department of nanomedicine at Houston Methodist Research Institute, explains that each component has a specific and essential role in the drug delivery process. The first component is the nanoporous silicon material that naturally degrades in the body. The second component is a polymer made up of multiple strands that contain doxorubicin. Once inside the tumor, the silicon material degrades, releasing the strands. Due to natural thermodynamic forces, these strands curl-up to form nanoparticles that are taken up by the cancer cells. Once inside the cancer cells, the acidic pH close to the nucleus causes the drug to be released from the nanoparticles. Inside the nucleus, the active drug acts to kill the cell.

“If this research bears out in humans and we see even a fraction of this survival time, we are still talking about dramatically extending life for many years. That’s essentially providing a cure in a patient population that is now being told there is none,” said Ferrari, who holds the Ernest Cockrell Jr. Presidential Distinguished Chair and is considered one of the founders of nanomedicine and oncophysics (physics of mass transport within a cancer lesion).

The Houston Methodist team is hopeful that this new drug could help cancer physicians cure lung metastases from other origins, and possibly primary lung cancers as well.

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Reporter: Ritu Saxena, Ph.D.

Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center Initiative.

Researchers at the MD Anderson Cancer center initiated a personalized medicine program by moving to phase I early clinical trials. The tumors were analyzed for molecular aberrations and matched with suitable targeted agents. Treatment assignment was not randomized. With a study involving 144 patients with advanced cancer stages, the authors found that the patients that underwent matched therapy based on their single aberration type, showed better results in terms of survival as compared to similar single aberration carrying patients who underwent systemic therapy (median, 13.4 vs. 9.0 months; p = 0.017).

The findings have been published a few days ago in the November 15th issue of Clinical Cancer Research Journal.

Abstract: Tsimberidou AM et al, Personalized medicine in a phase I clinical trials program: the MD anderson cancer center initiative. Clin Cancer Res. 2012 Nov 15;18(22):6373-83.

Authors’ Affiliations: Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program; and Departments of Hematopathology and Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

PURPOSE:

We initiated a personalized medicine program in the context of early clinical trials, using targeted agents matched with tumor molecular aberrations. Herein, we report our observations. Patient and Methods: Patients with advanced cancer were treated in the Clinical Center for Targeted Therapy. Molecular analysis was conducted in the MD Anderson Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Patients whose tumors had an aberration were treated with matched targeted therapy, when available. Treatment assignment was not randomized. The clinical outcomes of patients with molecular aberrations treated with matched targeted therapy were compared with those of consecutive patients who were not treated with matched targeted therapy.

RESULTS:

Of 1,144 patients analyzed, 460 (40.2%) had 1 or more aberration. In patients with 1 molecular aberration, matched therapy (n = 175) compared with treatment without matching (n = 116) was associated with a higher overall response rate (27% vs. 5%; P < 0.0001), longer time-to-treatment failure (TTF; median, 5.2 vs. 2.2 months; P < 0.0001), and longer survival (median, 13.4 vs. 9.0 months; P = 0.017). Matched targeted therapy was associated with longer TTF compared with their prior systemic therapy in patients with 1 mutation (5.2 vs. 3.1 months, respectively; P < 0.0001). In multivariate analysis in patients with 1 molecular aberration, matched therapy was an independent factor predicting response (P = 0.001) and TTF (P = 0.0001).

CONCLUSION:

Keeping in mind that the study was not randomized and patients had diverse tumor types and a median of 5 prior therapies, our results suggest that identifying specific molecular abnormalities and choosing therapy based on these abnormalities is relevant in phase I clinical trials.

Sources:

Research article by Tsimberidou AM et al. Clin Cancer Res. 2012 Nov 15;18(22):6373-83.

News brief by Virginia Postrel, a Bloomberg View Columnist, Cancer Breakthroughs Meet Market Realities, November, 2012.

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